Posttraumatic stress disorder (PTSD) is a debilitating and often chronic mental disorder that adversely affects daytime functioning and sleep during and after military deployment. Subjective reports of sleep complaints and objective indices of rapid-eye movement (REM) sleep disruption occurring early after trauma exposure are associated with increased risk of PTSD at follow-up assessments. Nightmares and insomnia are core features of PTSD, independently contribute to poor clinical outcomes, and are often resistant to psychological and pharmacological first-line interventions. These observations suggest that daytime PTSD symptoms may be partially mediated by REM sleep-specific mechanisms, and that these REM sleep-specific mechanisms are not normalized by recommended first-line treatments. However, the neurobiological correlates of PTSD during REM sleep remain unexplored. Waking neuroimaging studies in PTSD that used activation paradigms indicate that hyper-responsiveness of the amygdala to fear and threat-related stimuli, and /or impaired top-down inhibition of the amygdala by the medial prefrontal cortex characterize PTSD. Animal studies have shown that the amygdala and the medial prefrontal cortex are important modulators of sleep, via their interconnections with arousal-promoting regions of the brainstem basal forebrain, as well as with sleep-promoting regions and brainstem regions involved in the generation of REM sleep. Thus, changes in neuronal activity of the amygdala and medial prefrontal cortex reported in PTSD may have profound impact on neuronal activity of brain regions involved in REM sleep generation. The goal of this Exploratory/Developmental Research Grant Award (R21) is to explore the neurobiological correlates of PTSD during REM sleep by using state-of-the science sleep neuroimaging [18F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). Ten non-medicated military returnees from Operation Iraqi Freedom and Operation Enduring Freedom, who meet DSM-IV diagnostic criteria for PTSD, and who are between the ages of 21 and 45 years old will participate in this study. They will complete simultaneous polysomnographic (sleep) and PET studies during morning wakefulness and REM according to validated procedures. Ten age-matched combat-exposed military veterans without any psychiatric disorders will undergo the same assessments and PET procedures. In addition, data collected in PTSD subjects will be compared to archival data from age-matched patients with major depression to explore PTSD-specific cerebral metabolic changes during REM sleep. Findings derived from this exploratory study will provide new insights into the neurobiological correlates of PTSD during REM sleep, and will inform a subsequent, hypothesis-driven R01 proposal on the sleep neurobiological correlates of PTSD. Elucidating the neurobiological correlates of PTSD during REM sleep may also guide future efforts to identify the mechanisms underlying resistance of sleep disturbances to first-line treatments of PTSD and of other stress disorders. PUBLIC HEALTH RELEVANCE: Rapid-eye movement (REM) sleep is sensitive index of fear conditioning in animals, and is often disrupted in patients with posttraumatic stress disorder (PTSD). This study proposes to explore the neurobiological correlates of PTSD during REM sleep relative to wakefulness by using validated sleep neuroimaging methods in a sample of military returnees from Operation Iraqi Freedom and Operation Enduring Freedom with PTSD, and to compare patterns of changes in brain metabolic activity from wakefulness to REM sleep in veterans with PTSD to patterns of changes observed in age-matched combat- exposed veterans without PTSD and with patients with current major depression. Findings from the proposed study will provide new insights the neurobiological correlates of PTSD during both wakefulness and sleep.